02/17/2020

5:00-6:00 Intravenous Anesthethics

M Anesthesiology
LDT Meda Rose J. Luhan, M.D.

OUTLINE NON-OPIOID ANESTHETHICS: BARBITURATES

I. Overview Overview
II. Non-opioid Anesthetics
A. Barbiturates
B. Other Induction Agents
C. Benzodiazepines
III. Opioid Anesthetics
IV. Muscles Relaxants

OVERVIEW

Components of General Anesthesia

• Analgesia: loss of pain sensation • Barbituric acid

• Hypnosis: loss of consciousness o In pure form, it has no intrinsic CNS activity
• Blunting of reflexes o Substitutions at 2 and 5 carbon atoms produce drugs with
• Muscle relaxation CNS effects (loss of consciousness and anti-convulsant
activity)
Intravenous anesthetics • Mechanism of Action
o Acts at the synapses in the CNS
• Non-opioids o Facilitation of inhibitory transmitters (including GABA)
• Opioids o Blockade of excitatory transmitters (glutamic acid and
• Muscle relaxants acetylcholine)
• Has an anti-analgesic effect
Ideal Intravenous anesthetics • If analgesic was given with barbiturates, patient might feel pain
during surgery.
• Rapid onset without causing pain on injection
• Smooth on induction without twitching or excitement Thiopental
• Safe and cause minimal perturbation of the cardiovascular or
respiratory system • Not used anymore, replaced by propofol
• Short-acting • A sodium salt; alkaline with pH of 10.5 at 2.5% solution
• Rapid metabolism • Its alkalinity makes it incompatible with other drugs
o Extravasation is quite painful and causes skin necrosis
NON-OPIOID ANESTHETHICS o Must be injected into a free-flowing IV system

• Barbiturates Pharmacology
o Thiopental (no longer available in the market)
• Other Induction Agents • Given an IV bolus of 3-5mgs/kg
o Ketamine • When it reaches its peak concentration in the central circulation,
o Propofol we expect unconsciousness within 10-15 sec.
o Etomidate (not available in the Philippines) • Short duration of action is due to rapid redistribution of the drug
• Benzodiazepines • Elimination depends on metabolism (biotransformation in the
o Diazepam liver)
o Lorazepam • Excreted in the urine
o Midazolam
Clinical Effects

• CNS: Depresses cortical brain activity on EEGdecreases

intracranial pressure
• CVS: transient decrease in blood pressure with mild tachycardia;
has a negative inotropic effect; not used in hypovolemic patients
because it may lead to myocardial depression
• Respiratory: dose-dependent depression of medullary and
pontine respiratory system (the higher the dose, the greater the

CPU College of Medicine | Magnus Animus Medicus | 2021

 depression) following induction, the patient takes a large • Inactive metabolites  Less toxicity
breath then becomes apneic for a short period. • Causes reduction in BP without much in HR
• There may be incidence of apnea on induction
NON-OPIOID ANESTHETHICS: OTHER INDUCTION AGENTS o Make sure that the patient is well-ventilated; give oxygen
• Major advantage: rapid clearance and few residual effects on
Ketamine awakening  useful for outpatient procedures
(e.g. colonoscopy)
• An arylcyclohexylamine related to phencyclidine (PCP) • Induction agent, maintenance, or total IV agent
• Produces unique state called dissociative anesthesia • Purely IV anesthetics; no gases
(a cataleptic condition)
• Produces profound analgesia Etomidate
• Appear to be awake, eyes remain open, slow nystagmus
• Muscular activity appears purposeful; unaware; no recollection of • Not used in Philippines
events • Contains imidazole ring
• Water-soluble at acid pH and lipid-soluble at physiologic pH
Pharmacology • More rapid wakening
• Reduces cerebral blood flow, cerebral metabolism, and ICP
• Mechanism of Action • Stimulate seizure activity
o lamina-suppression of spinal cord activity that interrupts • Advantage: minimal impact on the hemodynamics (little change
transmission of the effective component of pain signals to the in BP, HR, CO)
brain
• Short duration of action due to redistribution NON-OPIOID ANESTHETHICS: BENZODIAZEPINES
• Norketamine: one of its metabolites that is responsible for
prolonging the CNS effects Overview
• Prolonged use induces hepatic metabolic enzymes and
tolerance develops • Uses:
• Respiratory depression is dose-dependent o Adjunct to General Anesthesia
• Relaxes bronchial smooth muscle (useful for asthmatics) o Premedication
• Excess oral secretion: prevented by antisialagogue (e.g. o Rarely used as induction agent
glycopyrrolate) • Produces amnesia but no analgesic properties
• Emergence delirium: 3-30% present with visual and auditory  Cannot eliminate pain
illusions; vivid unpleasant dreams  benzodiazepines prevent • Less cardiovascular and respiratory depression
delirium • Rare tolerance
• Midazolam: causes forgetfulness • Commonly used are:
 In children, unpleasant dreams may cause trauma and fear. o Diazepam
So, ketamine is combined with midazolam in order for them to o Lorazepam
forget. o Midazolam
• Floating sensations • Mechanism of action
o Act on the specific receptor sites in the postsynaptic nerves
Clinical effects in the CNS producing very little effect outside the CNS
o Sedation results from facilitation of the inhibitory
• Cardiovascular System neurotransmitters (GABA)
o Dose-related increase in HR and BP due to CNS stimulation • Flumazenil is the antagonist
o Indirect cardiovascular stimulation  useful in rapid- o All benzodiazepines are reversed by flumazenil
sequence induction of anesthesia in hypotensive patients
(trauma, pericarditis, tamponade) Diazepam
o Not used in patients with hypertension or coronary artery
disease • Insoluble in water
o May cause stroke or MI o oil-based that’s why it’s painful upon intramuscular injection
• Central Nervous System • Rapidly absorbed from the GIT (especially in children)
o Increase cerebral blood flow • Onset of action is slow and unpredictable
o Cause dangerous increase in intracranial pressure (should • Oxidative metabolism impaired by cimetidine
not be used in patients with brain tumors!) • Principal Uses:
o oral premedication
Propofol o IV sedation for regional anesthesia
o rarely used as induction agent
• New sedative-hypnotic intravenous agent
• It is similar to thiopental Lorazepam
• Reformulated as an aqueous emulsion of soybean oil, glycerol
and egg phosphatide  causes pain on injection • 5-10x potent than diazepam
o So prior to injection, Lidocaine or other analgesics is given • Reliably produces anterograde amnesia
• Unconsciousness in less than a minute • Less pain on injection, less phlebitis than diazepam

CPU College of Medicine | Magnus Animus Medicus | 2021 Page 2 of 7

 • IV and PO: reliably absorbed Analgesia, Brain +++ + +
• Principal Uses:
o anesthesia Ventilatory Depression +++ +/-
o rarely induction agent
Sedation ++ - +++
Midazolam
Reinforcement/dependence +++ +/-
 Commonly used in the Philippines Constipation +++ +/- +/-
 2-3x as potent as Diazepam
 Incorporates imidazole ring  making it stable in aqueous
solutions; painless on injection Agonist Activity of Available Opioids
 IM and oral route: rapid and dependable DRUGS
RECEPTOR
 IV route: peak effect at 3-5 minutes; 5 mgs of Midazolam will MU KAPPA
cause amnesia for 20-30 min
Morphine Agonist Agonist (weak)
 IM route: peak effect at 15-30 minutes
 Metabolism: liver; Excretion: urine
Fentanyl Agonist (potent) ---
 1-hydroxylmethylmidazolam: an active metabolite that
contributes to CNS effects Sufentanyl Agonist (potent) ---
 Principal Uses:
o anxiolytic Alfentanyl Agonist (potent) ---
o sedative amnestic drug
Meperidine Agonist Agonist (weak)
Clinical effects
Methadone Agonist ---
 CNS: decreases cerebral blood flow; does not worsen
diminished intracranial pressure Partial Agonist Partial Agonist
Buprenorphine
(Potent) (weak)
 Respiratory: dose dependent
 CVS: decrease BP, exaggerated in hypovolemic patients;
Partial Agonist
compensatory increase HR Nalbuphine Partial Agonist
(weak)

OPIOID IV ANESTHETHICS Butorphanol Partial Agonist Agonist

Overview Dezocine Partial Agonist ---

 Opiates Naloxone Agonist (potent) Antagonist (weak)

o Came from the juice of the unripe seed capsule of the poppy,
Papaver somniferum
Opioid Action
o Refers to drugs like codeine and morphine
 Opioids: any compounds that act on opioid receptors
 Analgesia
 3 distinct opioid receptors:
o Acts directly on spinal cord receptors
o Mu
o Inhibit transmission via dorsal horn between primary afferent
o Delta
neurons and the CNS
o Kappa
o Act on the thalamic and medullary centers to cause
 Opioid Receptors
descending inhibition of dorsal root activity
o Belong to superfamily of pharmacologic receptors that
 Effects specific to nociceptive (injury-perceiving) neurons
produce their cellular effects by interacting with guanine-
only
nucleotide binding proteins (G proteins)
o non-nociceptive afferents are unaffected (sensations of
o Receptors have diverse functions
pressure, touch, temperature are preserved)
o Widely distributed throughout the peripheral tissues and CNS
 Sedation
 Most of the actions of opioids commonly used in anesthesia can
o Large doses cause unconsciousness but do not produce true
be predicted from these receptors
lack of awareness
o Amnesia achieved with benzodiazepines, barbiturates or GA
 Ventilatory depression
o Opioids act on the mu receptors in the ventral medulla
EFFECTS OF OPIOID RECEPTORS o Inhibits stimulatory input of chemo-sensitive neurons into the
respiratory center
EFFECTS RECEPTORS o Opposed by pain and stimulation from noise, movement and
touch
MU DELTA KAPPA
o Closed observation of respiration and oxygenation at the
Analgesia, Spinal Cord +++ ++ ++ recovery room must be done.

CPU College of Medicine | Magnus Animus Medicus | 2021 Page 3 of 7

 o Patient may have a delayed response to opioid so respiratory
depression can occur late while the patient is in the recovery
room.
o Opposed cough reflex: useful during tracheal intubation for
smooth induction and emergence.
 Gastrointestinal Effects
o Nausea and Vomiting
Immediately observed post-op
Risk for aspiration
Give anti-emetic as premedication to prevent post-op
nausea or vomiting and aspiration.
Effect mediated by opioid stimulation of the
chemoreceptor trigger zone (CTZ) at the 4th ventricle
Scopolamine or other centrally acting anti-muscarinics
counteract opioid-induced nausea and vomiting
o Constipation
Results from activation of receptors from the spinal cord to
the gut
Precipitate biliary colic (this complicates cholangiogram)
 Cardiovascular Effects
o Analgesic dose: has little direct effect on cardiovascular
function in awake and healthy patients
o Larger dose + other anesthetics: depress blood circulation
o Bradycardia is treated with muscarinics (atropine).
o Hypotension upon morphine intake is due to histamine
release that causes vasodilation.
o Opioids + Volatiles  decrease BP and HR
 Motor Effects
o Causes muscle rigidity due to increased activity on the
central motor pathway
o Chest wall rigidity prevent adequate ventilation
o Involvement of muscle in the neck and head cause difficulty
in intubation
o These effects can be overcome by neuromuscular blockade
(muscle relaxants)
Reinforcement, Tolerance, Dependence, and Addiction
 These anesthetics have a potential for abuse.
 Supposedly for pain relief only
 Tolerance and dependence: may arise in patients after a period
of exposure to opioid agonists
 Tolerance: a requirement for increasing amounts of drug to
achieve the original effects; potency decreases
 Dependence: a state of adaptation to the drug so that the drug
is required to function normally and its absence causes the
syndrome of abstinence or withdrawal
 Addiction: compulsive use of substance; intense preoccupation
with obtaining it and a strong tendency to relapse
 These drugs require “yellow pad” from anesthesiologists
and are regulated by PDEA.
Other Effects
 Miosis: disinhibition of the Edinger-Westphal nucleus
 Pruritus: results from activation of central opioid receptors or
histamine release
 True allergy: rare
 Responds to small doses of naloxone or antihistamines
CPU College of Medicine | Magnus Animus Medicus | 2021
Morphine
 Histamine release: a distinguishable feature
o Causes peripheral vasodilatation, hypotension, reflex
tachycardia, cutaneous flushing
Treatment: give slowly or in divided doses
o H1 and H2 blockers: blunt the histamine-mediated
cardiovascular effects of morphine
 Metabolized primarily to morphine-3-glucoronide and morphine-
6-glucoronide
 Morphine-6-glucoronide is the one that contributes to the clinical
effects of morphine
 Excreted by the kidneys
Fentanyl
 More potent than morphine
 Small IV dose: rapid onset of action
 High doses: profound analgesia and sedation, slow recovery of
ventilator function; better tolerated due to lack of histamine
release
 Most useful drug for opioid-based anesthesia for patients
undergoing surgery
Sufentanyl
 Not available in the Philippines
 Extremely potent synthetic opioid (7x more potent than fentanyl)
 The most selective opioid for the mu receptor available for
clinical use
Alfentanyl
 Not available in the Philippines
 Potency is 1/175 of fentanyl
 Ultra short-acting
 Has little advantage over fentanyl and sufentanyl
Meperidine
 Brand name: Demerol (Pethidine in UK and Australia)
 The first completely synthetic opioid
 Potency is 1/10 of morphine
 Duration of action: between fentanyl and morphine’s DOA
 Elimination half-life: 3 hours (similar to morphine)
 Metabolite: Normepiridine (neurotoxic in greater concentration)
 Excreted by the kidney
 Seizures can occur in large doses
 Meperidine + Monoamine oxidase inhibitors (causes fatal
excitatory state- hypertension, tachycardia, delirium, seizures,
hyperpyrexia)
 Given to control shivering
Mixed Agonist-Antagonist
 Has the ability to produce opioid agonist effects when given
alone but has antagonizing effects of morphine when
administered together with:
o Butorphanol
o Nalbuphine
o Pentazocine
 Both Butorphanol and Nalbuphine are available in the Philippines
Page 4 of 7
  When your patient is given morphine in subarachnoid route
during a cesarian section, do not give Butorphanol or
Nalbuphine post-op because they antagonize each other.
Antagonist
 Naloxone (Narcan)
o Opioid antagonist is common in clinical use
o Competitive antagonist in all 3 receptors but most potent at
the mu receptor
o Reverses opioid toxicity or overdose after anesthesia
o Counteracts some side effects of spinal opioids
o Given in IV
o Not given to opioid-dependents
 this precipitates severe withdrawal and suffering
 Naltrexone
o Long-acting opioid antagonist
o Given PO for maintenance of abstinence in former opioid
addicts
o Not available in the Philippines
MUSCLE RELAXANTS
Background
 Important part of anesthesia management in the OR
 Surgeries require excellent skeletal muscle relaxation
 Helpful especially in abdominal procedures
 1940s:
o D-tubocurarine (first discovered muscle relaxant)
o Metocurine and Pancuronium (long-acting muscle relaxants)
o Atracurium and Vecuronium (modern medicines)
o Rocuronium (the most modern; currently use in the clinics)
 The development of muscle relaxants with more rapid onset,
shorter duration, and predictable outcome with minimal side
effects still continues.
Neuromuscular Pharmacology and Physiology
 Muscle relaxants produce desired effect at the neuromuscular
junction (NMJ)
 Nonspecific effects at many other sites
 Neuromuscular junction (NMJ)
o Also known as myoneuronal junction
o is a chemical synapse formed by the contact between a
motor neuron and a muscle fiber
o is the site that a motor neuron is able to transmit a signal to
the muscle fiber, causing muscle contraction
CPU College of Medicine | Magnus Animus Medicus | 2021
Neuromuscular Transmission
 Step 1: Nerve impulse arrives of axon terminal of motor neuron
and triggers release of acetylcholine (ACh)
 Step 2: Ach diffuses, binds to the receptors, and triggers muscle
action potential
 Step 3: Acetylcholinesterase destroys Ach, so, more action
potentials do not arise
 Step 4: Action potential traveling along T tubule opens Ca2+ ion
channels in the sarcoplasmic reticulum. Then, Ca2+ enters into
the sarcoplasm.
 Step 5: Ca2+ binds to troponin
 Step 6: Contraction
 Step 7: Ca2+ ion channels close and calcium transport pumps
use ATP to restore low levels of calcium in sarcoplasm
 Step 8: Troponin complex returns to original position to block
myosin binding sites on actin
 Step 9: Muscle Relaxes
DEPOLARIZING MUSCLE RELAXANTS
Succinylcholine
Uses:
 SCh is the only depolarizing NMBD used clinically.
 Furthermore, it is the only NMBD with both a rapid onset and
ultrashort duration of action.
 Typically, doses of 0.5 to 1.5 mg/kg intravenously are
administered and produce a rapid onset of skeletal muscle
paralysis (30 to 60 seconds) that lasts 5 to 10 minutes because
of its unique breakdown
Pharmacokinetics:
 SCh mimics the action of ACh and produces a sustained
depolarization of the postjunctional membrane.
 Skeletal muscle paralysis occurs because a depolarized
postjunctional membrane and inactivated sodium channels
cannot respond to subsequent release of ACh (hence, the
designation depolarizing neuromuscular blockade). Depolarizing
neuromuscular blockade is also referred to as phase I blockade.
 Phase II blockade is present when the postjunctional membrane
has become repolarized but still does not respond normally to
ACh (desensitization neuromuscular blockade). The mechanism
of phase II blockade is unknown but may reflect the development
of nonexcitable areas around the end plates that become
repolarized but nevertheless prevent the spread of impulses
initiated by the action of ACh.
 With the initial dose of SCh, subtle signs of a phase II blockade
begin to appear (fade to tetanic stimulation).
 Phase II blockade, which resembles the blockade produced by
nondepolarizing NMBDs, predominates when the dose of SCh
exceeds 3 to 5 mg/kg IV
Page 5 of 7

NON-DEPOLARIZING MUSCLE RELAXANTS
General Pharmacokinetics
Nondepolarizing NMBDs, because of their quaternary ammonium
groups, are highly ionized, water-soluble compounds at
physiologic pH and possess limited lipid solubility. As a result,
these drugs cannot easily cross lipid membrane barriers, such as
the blood-brain barrier, renal tubular epithelium, gastrointestinal
epithelium, or placenta. Therefore, nondepolarizing NMBDs do not
pro- duce central nervous system effects, renal tubular reab-
sorption is minimal, oral administration is ineffective, and maternal
administration does not adversely affect the fetus.
Long-Acting
 Pancuronium
o bisquaternary aminosteroid nondepolarizing NMBD with an
ED95 of 70 mg/kg; it has an onset of action of 3 to 5 minutes
and a duration of action of 60 to 90 minutes
o Cardiovascular effects
 typically produces a modest 10% to 15% increase in heart
rate, mean arterial pressure, and cardiac output.
 The increase in heart rate reflects pancuronium-induced
selective blockade of cardiac muscarinic receptors
(atropine-like effect), principally in the sinoatrial node
 Histamine release and autonomic ganglion blockade are not
produced by pancuronium.
CPU College of Medicine | Magnus Animus Medicus | 2021
Intermediate Acting
 Rocuronium
o monoquaternary aminosteroid nondepolarizing NMBD with an
ED95 of 0.3 mg/kg that has an onset of action of 1 to 2
minutes and a duration of action of 20 to 35 minutes.
o The lack of potency of rocuronium in comparison to
vecuronium is an important factor in determining the rapid
onset of neuromuscular blockade produced by this NMBD.
o the large doses of rocuronium (3 to 4 " ED95) needed to
mimic the onset time of SCh produce a duration of action
resembling that of pancuronium.
o Clearance of rocuronium is largely as unchanged drug in bile,
with deacetylation not occurring.
o Renal excretion of the drug may account for as much as 30%
of a dose, and administration of this drug to patients in renal
failure could result in a longer duration of action, especially
with repeated doses or prolonged intravenous infusion.
 Vecuronium
o a monoquaternary aminosteroid nondepolarizing NMBD with
an ED95 of 50 mg/kg that produces an onset of action of 3 to
5 minutes and a duration of action of 20 to 35 minutes
o This drug undergoes both hepatic and renal excretion.
o Metabolites are pharmacologically inactive, with the
exception of 3-desacetylvecuronium, which is approxi-
mately 50% to 70% as potent as the parent compound.
o The increased lipid solubility of vecuronium as compared with
pancuronium also facilitates biliary excretion of vecuronium.
The effect of renal failure on the duration of action of
vecuronium is small, but repeated or large doses may result
in prolonged neuromuscular blockade.
o Vecuronium is typically devoid of circulatory effects,
emphasizing its lack of vagolytic effects (pancuronium) or
histamine release (atracurium).
 Atracurium
o bisquaternary benzylisoquinolinium nondepolarizing NMBD
(mixture of 10 stereoisomers) with an ED95 of 0.2 mg/kg that
produces an onset of action of 3 to 5 minutes and a duration
of action of 20 to 35 minutes
o Clearance of this drug is by a chemical mechanism
(spontaneous nonenzymatic degradation at normal body
temperature and pH known as Hofmann elimination) and a
biologic mechanism (ester hydrolysis by nonspecific plasma
esterases).
o Laudanosine is the major metabolite of both pathways. This
metabolite is not active at the NMJ but may, in high,
nonclinical concentrations, cause central nervous system
stimulation.
o Because of histamine release with larger doses, atracurium
can cause hypotension and tachycardia. However, doses
smaller than 2 " ED95 rarely cause cardiovascular effects.
 Cisatracurium
o benzylisoquinolinium nondepolarizing NMBD with an ED95 of
50 mg/kg that has an onset of action of 3 to 5 minutes and a
duration of action of 20 to 35 minutes
Page 6 of 7
 o In contrast to atracurium, non- specific plasma esterases do
not seem to be involved in the clearance of cisatracurium.
o Cisatracurium is often used in patients undergoing renal
transportation.
o Cisatracurium, in contrast to atracurium, is devoid of
histamine-releasing effects
o cardiovascular changes do not accompany the rapid
intravenous administration of even large doses of
cisatracurium
Short- Acting
 Mivacurium
o a benzylisoquinolinium nondepolarizing NMBD with an ED95
of 80 mg/kg that has an onset of action of 2 to 3 minutes and
a duration of action of 12 to 20 minutes
o the duration of action of mivacurium is approxi- mately twice
that of SCh and 30% to 40% that of the inter- mediate-acting
nondepolarizing NMBDs.
CPU College of Medicine | Magnus Animus Medicus | 2021
DEPOLARIZING VS. NON-DEPOLARIZING
 Depolarizing muscle relaxants acts as ACh receptor agonists.
They bind to the ACh receptors and generate an action
potential. However, because they are not metabolized by
acetylcholinesterase, the binding of this drug to the receptor is
prolonged resulting in an extended depolarization of the
muscle end-plate. As the muscle relaxant continues to bind to
the ACh receptor, the end plate cannot repolarize, resulting in
a phase I block. The ACh receptor can also undergo
conformational and ionic changes after a period of time,
resulting in a phase II block.
 Nondepolarizing muscle relaxants act as
competitive antagonists. They bind to the ACh receptors but
unable to induce ion channel openings. They prevent ACh from
binding and thus end plate potentials do not develop.
SOURCES
 Powerpoint
 Audio Recordings
APPENDIX
Page 7 of 7